    1. Branchek, T. A., et al. (2000). Annu Rev Pharmacol Toxicol 40: 319-34.    2. Monsma, F. J., Jr., et al. (1993). Mol Pharmacol 43(3): 320-7.    3. Ruat, M., et al. (1993). Biochem Biophys Res Commun 193(1): 268-76.    4. Kohen, R., et al. (1996). J Neurochem 66(1): 47-56.    5. Ward, R. P., et al. (1996). J Comp Neurol 370(3): 405-14.    6. Ward, R. P., et al. (1995). Neuroscience 64(4): 1105-11.    7. Gerard, C., et al. (1997). Brain Res 746(1-2): 207-19.    8. Gerard, C., et al. (1996). Synapse 23(3): 164-73.    9. Glennon, R. A., et al. (2000). J Med Chem 43(5): 1011-8.    10. Roth, B. L., et al. (1994). J Pharmacol Exp Ther 268(3): 1403-10.    11. Sleight, A. J., et al. (1998). Br J Pharmacol 124(3): 556-62.    12. Routledge, C., et al. (2000). Br. J. Pharmacol. 130(7): 1606.    13. Hirst, W. D., et al. (1999). Br. J. Pharmacol. Suppl. ((in press)).    14. Hirst, W. D., et al. (2000). Br. J. Pharmacol. 130: 1597.    15. Bourson, A., et al. (1995). J Pharmacol Exp Ther 274(1): 173-80.    16. Bentley, J. C., et al. (1999). Br J Pharmacol 126(7): 1537-42.    17. Bourson, A., et al. (1998). Br J Pharmacol 125(7): 1562-6.    18. Routledge, C., et al (1999). Br. 3. Pharmacol. 127(Suppl.): 21P.    19. Goldberg, T. E., et al. (1993). Br J Psychiatry 162: 43-8.    20. Hagger, C., et al. (1993). Biol Psychiatry 34(10): 702-12.    21. Lee, M. A., et al. (1994). J Clin Psychiatry 55 Suppl B: 82-7.    22. Purdon, S. E., et al. (2000). Arch Gen Psychiatry 57(3): 249-58.    23. Parada, M. A., et al. (1997). 3 Pharmacol Exp Ther 281(1): 582-8.    24. Rogers, D. C., et al. (1999). Br J Pharamcol 127(suppl.): 22P.    25. Dawson, L. A., et al. (2000). Br J Pharmacol 130(1): 23-6.    26. Dudkin, K. N., et al. (1996). Neurosci Behav Physiol 26(6): 545-51.    27. Koechlin, B., et al. (1999). Nature 399(6732): 148-51.            The present invention provides compounds of formula I:        
wherein    X is selected from the group consisting of —O—, —NH—, —S—, —SO2—, —CH2—, —CH(F)—, —CH(OH)—, and —C(O)—;    R1 is selected from the group consisting of optionally substituted phenyl, optionally substituted naphthyl, optionally substituted 5 to 6 membered monocyclic aromatic heterocycle having one heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur and which 5 to 6 membered monocyclic aromatic heterocycle is optionally benzofused;    R2 is selected from the group consisting of hydrogen and C1-C3 alkyl;    R3 is selected from the group consisting of hydrogen, fluoro, and methyl;    R4 is selected from the group consisting of hydrogen, allyl, C2-C4 alkyl, fluorinated C2-C4 alkyl, optionally substituted phenyl, optionally substituted phenylsulfonyl, optionally substituted benzyl, and optionally substituted 5 to 6 membered monocyclic aromatic heterocycle having one or two heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, provided that R4 is not optionally substituted phenylsulfonyl when X is —SO2—, CH2—, —CH(F)—, —CH(OH)—, or —C(O)—; andpharmaceutically acceptable salts thereof.The present invention also provides compounds of formula II:
wherein    Y is selected from the group consisting of O, NH, and NR9, wherein R9 is selected from the group consisting of C1-C4 alkyl, and optionally substituted phenyl;    R5 and R6 are hydrogen or taken together with the atoms to which they are attached form a benzo ring, provided that R5 and R6 are hydrogen when Y is NR9;    R7 is selected from the group consisting of optionally substituted phenyl, optionally substituted naphthyl, optionally substituted 5 to 6 membered monocyclic aromatic heterocycle having one heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur and which 5 to 6 membered monocyclic aromatic heterocycle is optionally benzofused;    R8 is selected from the group consisting of hydrogen and C1C3 alkyl; and pharmaceutically acceptable salts thereof.
The present invention also provides for novel pharmaceutical compositions, comprising: a compound of the formula I or II and a pharmaceutically acceptable diluent.
Because the compounds of formula I and II are antagonists of 5-HT6 receptor, the compounds of formula I and II are useful for the treatment of a variety of disorders. Thus, in another embodiment the present invention provides methods of treating disorders associated with 5-HT6, comprising: administering to a patient in need thereof an effective amount of a compound of formula I or II. That is, the present invention provides for the use of a compound of formula I or II and pharmaceutical compositions thereof for the treatment disorders associated with 5-HT6. More specifically, the present invention provides a method of treating disorders selected from the group consisting of cognitive disorders, age-related cognitive disorder, mild cognitive impairment, mood disorders (including depression, mania, bipolar disorders), psychosis (in particular schizophrenia), anxiety (particularly including generalized anxiety disorder, panic disorder, and obsessive compulsive disorder), idiopathic and drug-induced Parkinson's disease, epilepsy, convulsions, migraine (including migraine headache), substance withdrawal (including, substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.), sleep disorders (including narcolepsy), attention deficit/hyperactivity disorder, conduct disorder, learning disorders, dementia (including Alzheimer's disease and AIDS-induced dementia), Huntington's Chorea, cognitive deficits subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, and hypoglycemic neuronal damage, vascular dementia, multi-infarct dementia, amylotrophic lateral sclerosis, and multiple sclerosis, comprising: administering to a patient in need thereof an effective amount of a compound of formula I or an effective amount of a compound of formula II.
In addition, the present invention also provides processes for preparing the compounds of formula I and II and intermediate thereof.
As used herein, the following terms have the meanings indicated:
The term “C1-C3 alkyl” refers to a straight or branched alkyl chain having from one to three carbon atoms, and includes methyl, ethyl, propyl, and iso-propyl.
The term “optionally substituted phenyl” refers to a radical of the formula

wherein Ra is from 1 to 3 groups independently selected from the group consisting of hydrogen, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, halogen, benzyloxy, carboxy, C1-C4 alkoxycarbonyl, amido, N—C1-C4 alkyl)amido, sulfonylamido, cyano, trifluoromethyl, trifluoromethoxy, nitro, and phenyl optionally substituted with C1-C4 alkyl, C1-C4 alkoxy, halogen, cyano, and trifluoromethyl.
The term “optionally substituted naphthyl” refers to a radical of the formula

wherein Rc is from 1 to 2 groups independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, cyano, trifluoromethyl, and nitro.
The term “optionally substituted 5 to 6 membered monocyclic aromatic heterocycle having one heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur and which 5 to 6 membered monocyclic aromatic heterocycle is optionally benzofused” refers to radicals of the formula
wherein Q1 is selected from the group consisting of —O—, —S—, and —NRg— wherein Rg is selected from the group consisting of hydrogen and C1-C4 alkyl; and Q2 is —N═, Rd, each Re, and Rf are each independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, cyano, and trifluoromethyl, or Rd and Re (or one of Re) are taken together with the atoms to which they are attached to form an benzo ring which benzo ring is optionally substituted with 1 to 4 substituents independently selected from the group consisting of hydrogen, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, trifluoromethyl, halogen, carboxy, C1-C4 alkoxycarbonyl, amido, N—(C1-C4 alkyl)amido, amino, (C1-C4 alkyl)amino, acylamino wherein the acyl group is selected from the group consisting of C1-C4 alkyl and phenyl; cyano, nitro, sulfonylamido, phenyl optionally substituted with C1-C4 alkyl, C1-C4 alkoxy, halogen, cyano, and trifluoromethyl; phenoxy, benzyloxy, —NHS(O)2Rh, wherein Rh is selected from the group consisting of C1-C4 alkyl and phenyl; and —S(O)pRi, wherein p is 0, 1, or 2 and Ri is selected from the group consisting of C1-C4 alkyl and phenyl optionally substituted with C1-C4 alkyl, C1-C4 alkoxy, halogen, cyano, and trifluoromethyl; and Rf is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, trifluoromethyl, and halogen. The term specifically includes furyl, thienyl, pyrrolyl, pyridyl, benzofuryl, benzothienyl, indolyl and quinolinyl; each optionally substituted as described above.
The term “fluorinated C2-C4 alkyl” refers to a straight or branched alkyl chain having from two to four carbon atoms substituted with one or more fluorine atoms. The term includes 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3-fluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, 2,2,3,3,3-pentafluoropropyl, 2,2,3,3-tetrafluoropropyl, 4,4,4-trifluorobutyl, 3,3,4,4,4-pentafluorobutyl, and the like.
The term “optionally substituted phenylsulfonyl” refers to a radical of the formula

wherein Rj is from 1 to 3 groups independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, cyano, trifluoromethyl, nitro, and phenyl.
The term “optionally substituted benzyl” refers to a radical of the formula

wherein Rk is form 1 to 3 groups independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, cyano, nitro, trifluoromethyl, and halogen.
The term “optionally substituted 5 to 6 membered monocyclic aromatic heterocycle having one or two heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur” refers to radicals of the formula
wherein Q3 is selected from the group consisting of —O—, —S—, and —NRg— wherein Rg′ is selected from the group consisting of hydrogen and C1-C4 alkyl; and Q4 and Q5 are —CRm, wherein each Rm is independently selected from the group consisting of hydrogen, C1-C4 alkyl, halogen, and trifluoromethyl or one or both of Q4 and Q5 is —N═; and wherein one or two of Q6 are —N═, while the others are CRn; wherein each Rn is independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, cyano, nitro, and trifluoromethyl. The term specifically includes furyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, isoxazolyl, thioisoxazolyl, pyridyl, pyrimidyl, pyridazinyl, and pyrazidinyl; each optionally substituted as described above.
The term “C1-C4 alkyl” refers to a straight or branched alkyl chain having from one to four carbon atoms, and includes methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, iso-butyl, and t-butyl.
The term “C2-C4 alkyl” refers to a straight or branched alkyl chain having from two to four carbon atoms, and includes ethyl, propyl, iso-propyl, butyl, sec-butyl, iso-butyl, and t-butyl.
The term “C1-C4 alkoxy” refers to a straight or branched alkyl chain having from one to four carbon atoms attached to an oxygen atom, and includes methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy, sec-butoxy, and t-butoxy.
The term “halogen” refers to a chloro, fluoro, bromo or iodo atom.
The term “pharmaceutically-acceptable addition salt” refers to an acid addition salt.
The compound of formula I or II and the intermediates described herein form pharmaceutically acceptable acid addition salts with a wide variety of organic and inorganic acids and include the physiologically acceptable salts which are often used in pharmaceutical chemistry. Such salts are also part of this invention. A pharmaceutically-acceptable addition salt is formed from a pharmaceutically-acceptable acid as is well known in the art. Such salts include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2-19 (1977) which are known to the skilled artisan. Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydriodic, nitric, sulfuric, phosphoric, hypophosphoric, metaphosphoric, pyrophosphoric, and the like. Salts derived from organic acids, such as aliphatic mono and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, may also be used. Such pharmaceutically acceptable salts thus include chloride, bromide, iodide, nitrate, acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, isobutyrate, phenylbutyrate, α-hydroxybutyrate, butyne-1,4-dicarboxylate, hexyne-1,4-dicarboxylate, caprate, caprylate, cinnamate, citrate, formate, fumarate, glycollate, heptanoate, hippurate, lactate, malate, maleate, hydroxymaleate, malonate, mandelate, mesylate, nicotinate, isonicotinate, oxalate, phthalate, teraphthalate, propiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, suberate, benzenesulfonate, p-bromobenzenesulfonate, chlorobenzenesulfonate, ethylsulfonate, 2-hydroxyethylsulfonate, methylsulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, naphthalene-1,5-sulfonate, p-toluenesulfonate, xylenesulfonate, tartrate, and the like.
As with any group of pharmaceutically active compounds, some groups are preferred in their end use application. Preferred embodiments of the present invention are given for the compounds of formula I below:
Compounds in which wherein X is selected from the group consisting of —O—, —NH—, and —S— are preferred, with compounds in which X is —O— being more preferred.
Compounds in which R1 is optionally substituted phenyl or optionally substituted 5 to 6 membered monocyclic aromatic heterocycle having one heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur and which 5 to 6 membered monocyclic aromatic heterocycle is optionally benzofused are preferred.
When R1 is optionally substituted phenyl preferred substituents are 1 to 3 groups independently selected from the group consisting of hydrogen, C1-C4 alkyl, halogen, benzyloxy, carboxy, C1-C4 alkoxycarbonyl, amido, N—(C1-C4 alkyl)amido, sulfonylamido, cyano, trifluoromethyl, trifluoromethoxy, nitro, and phenyl optionally substituted with C1-C4 alkyl, C1-C4 alkoxy, halogen, cyano, and trifluoromethyl.
When R1 is optionally substituted phenyl more preferred substituents are 1 to 3 groups independently selected from the group consisting of hydrogen, C1-C4 alkyl, halogen, cyano, and trifluoromethyl.
Compounds in which R3 is hydrogen or fluorine are preferred.
Compound in which R1 is optionally substituted 5 to 6 membered monocyclic aromatic heterocycle having one heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur and which 5 to 6 membered monocyclic aromatic heterocycle is optionally benzofused, the compounds which are benzo fused are preferred, with indolyl being preferred, and indol-3-yl being even more preferred.
When R1 is indol-3-yl, preferred groups are depicted as the radical below:
    a) Ro is selected from the group consisting of hydrogen and C1-C4 alkyl, with hydrogen being more preferred;    b) Rp is selected from the group consisting of hydrogen and C1-C4 alkyl, with hydrogen being more preferred;    c) Rq is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, and halogen, with hydrogen being more preferred;    d) Rq′ is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, trifluoromethyl halogen, and —S(O)pRi wherein p is 2 and R1 is phenyl optionally substituted with C1-C4 alkyl, C1-C4 alkoxy, trifluoromethyl, with halogen being more preferred;    e) Rq″ is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, nitro, cyano, trifluoromethyl, and —S(O)pRi, wherein p 2 and R1 is phenyl optionally substituted with C1-C4 alkyl, with halogen being more preferred; and    f) Rq″ is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, trifluoromethyl, cyano, and nitro, with hydrogen and halogen being preferred.
Compounds in which R4 is selected from the group consisting of C2-C4 alkyl, fluorinated C2-C4 alkyl and optionally substituted phenyl are preferred.
When R4 is C2-C4 alkyl, particularly preferred groups include propyl, isopropyl, and butyl.
When R4 is fluorinated C2-C4 alkyl, preferred groups include 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3-fluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, 2,2,3,3,3-pentafluoropropyl, and 2,2,3,3-tetrafluoropropyl.
When R4 is optionally substituted phenyl preferred groups include 1 to 3 groups independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, cyano, and trifluoromethyl.
Preferred embodiments of the present invention are given for the compounds of formula II below:
Compounds in which R7 is optionally substituted phenyl or optionally substituted 5 to 6 membered monocyclic aromatic heterocycle having one heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur and which 5 to 6 membered monocyclic aromatic heterocycle is optionally benzofused are preferred.
When R7 is optionally substituted phenyl preferred substituents are 1 to 3 groups independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, cyano, trifluoromethoxy, and trifluoromethyl.
Compounds in which R7 is optionally substituted 5 to 6 membered monocyclic aromatic heterocycle having one heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur and which 5 to 6 membered monocyclic aromatic heterocycle is optionally benzofused, the compounds which are benzo fused are preferred, with indolyl being preferred, and indol-3-yl being even more preferred, with the indol-3-yl depicted above for formula I being more preferred.
Preferred compounds of formula II having the points of attachment depicted below:

While only compounds of formula I are depicted, the compounds of formula I and II are prepared as described in Schemes A and B below. In the Schemes below all substituents, unless otherwise indicated, are as previously defined, and all starting materials and reagents are well known and appreciated in the art and readily available or prepared by methods described herein. In the Schemes below, it is understood that protecting groups can be used, where appropriate to allow for elaboration of a portion of the compounds Of formula I or II. The selection, use, and removal of suitable protecting groups is well known and appreciated in the art (Protecting Groups in Organic Synthesis, Theodora Greene (Wiley-Interscience)).

Scheme A depicts alternative methods for the preparation of compounds of formula I by reductive amination.
In one alternative of Scheme A, step a, an appropriate compound of formula (1) is contacted with an appropriate compound of formula (2) in a reductive amination reaction to give a compound of formula I. An appropriate compound of formula (1) is one in which R1 and R2 are as desired in the final product of formula I or give rise to groups desired in the final product of formula I. An appropriate compound of formula (2) is one in which X, R3, and R4 are as desired in the final product of formula I, or give rise to groups desired in the final product of formula I.
In another alternative of Scheme A, step a, an appropriate compound of formula (3) is contacted with an appropriate compound of formula (4) in a reductive amination reaction to give a compound of formula I. An appropriate compound of formula (3) is one in which R1 and R2 are as desired in the final product of formula I or give rise to groups desired in the final product of formula I. An appropriate compound of formula (4) is one in which X, R3, and R4 are as desired in the final product of formula I, or give rise to groups desired in the final product of formula I.
The reductive amination depicted in Scheme A, step a, can be carried out under a variety of conditions, such as by hydrogenation using a suitable catalyst or using a suitable reducing agent.
For example, an appropriate amine of formula (1) is contacted with an appropriate aldehyde of formula (2) (or alternately an appropriate amine of formula (4) and an appropriate aldehyde of formula (3)) and a suitable reducing agent to give a compound of formula I. The reaction is carried out in a suitable solvent, such as methanol, ethanol, tetrahydrofuran, or mixtures of methanol or ethanol and tetrahydrofuran, dichloromethane, and 1,2-dichloroethane. The reaction may be carried out in the presence of a drying agent, such as sodium sulfate, cupric sulfate, or molecular sieves. The reaction is carried out in the presence of from about 1 to 20 molar equivalents of a suitable reducing agent, such as, sodium borohydride, sodium cyanoborohydride, and sodium triacetoxyborohydride. It may be advantageous to allow Schiff base formation to proceed before addition of the suitable reducing agent. When sodium cyanoborohydride is used it may be advantageous to monitor and adjust the pH during the course of the reaction as is known in the art. The reaction is generally carried out at temperatures of from 0° C. to the refluxing temperature of the solvent. Generally, the reactions require 1 to 72 hours. The product can be isolated and purified by techniques well known in the art, such as filtration, extraction, evaporation, trituration, chromatography, and recrystallization.
Scheme A, optional step b, not shown, an acid addition salt of a compound of formula I is formed using a pharmaceutically-acceptable acid. The formation of acid addition salts is well known and appreciated in the art.

Scheme B depicts alternative methods for the preparation of compounds of formula I by formation and reduction of an amide.
In one alternative, Scheme B, step a, depicts contacting an appropriate compound of formula (1) with an appropriate compound of formula (5) in a amide forming reaction to give a compound of formula (6). An appropriate compound of formula (1) is as described in Scheme A. An appropriate compound of formula (5) is one in which A is an activating group, talking the form of an acid halide, activated ester, activated amide, or anhydride, and X, R3, and R4 are as desired in the final product of formula I, or give rise to groups desired in the final product of formula I.
In another alternative, Scheme B, step a, depicts contacting an appropriate compound of formula (7) with an appropriate compound of formula (4) in a amide forming reaction to give a compound of formula (8). An appropriate compound of formula (7) is one in which A is an activating group as described above and R1 is as desired in the final product of formula I. An appropriate compound of formula (4) is as described in Scheme A. Appropriate compounds of formula (4) and (7) are generally available from commercial sources and can also be prepared by methods described herein and by methods described in the art.
The amide formation reaction depicted in Scheme B, step a, is readily accomplished by a number of methods readily available to the skilled person, including those which are conventionally conducted for peptide synthesis. Such methods can be carried out on the acid, acid halide, activated esters, activated amides, and anhydrides.
For example, well known coupling reagents such as a carbodiimides with or without the use of well known additives such as N-hydroxysuccinimide, 1-hydroxybenzotriazole, etc. can be used to facilitate amide formation. Such coupling reactions are typically use about 1 to 1.5 molar ratios of acid, amine, and coupling reagent and are conventionally conducted in an inert aprotic solvent such as pyridine, dimethylformamide, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, tetrahydrofuran and the like. It may be advantageous to use a suitable base, such as triethylamine or N,N-diisopropylethylamine, in such coupling reactions. The reaction is preferably conducted at from about 0° C. to about 60° C. until reaction completion which typically occurs within 1 to about 48 hours. Upon reaction completion, the product can be isolated and purified by techniques well known in the art, such as filtration, extraction, evaporation, trituration, chromatography, and recrystallization.
Alternatively, for example, an acid halide can be employed in the reaction. It may be advantageous to use a suitable base to scavenge the acid generated during the reaction, suitable bases include, by way of example, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, pyridine, and the like. Typically, about 1 to 1.5 molar ratios of the acid halide and amine are used. The reaction can be carried out in a variety of inert aprotic solvents such as pyridine, dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, and the like. The reaction is preferably conducted at from about 0° C. to about 60° C. until reaction completion which typically occurs within 1 to about 12 hours. Upon reaction completion, the product can be isolated and purified by techniques well known in the art, such as filtration, extraction, evaporation, trituration, chromatography, and recrystallization.
Alternatively, for example, an acid halide can be employed in the reaction under Schotten-Baumann conditions. Typically, under such conditions 1 to 10 molar equivalents of amine are used. Such couplings generally use a suitable base to scavenge the acid generated during the reaction, such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and the like. The reaction can be carried out in a variety of mixed solvent systems such as dichloromethane, chloroform, ethyl acetate, tetrahydrofuran and the like; and water. The reaction is preferably conducted at from about 0° C. to about 80° C. until reaction completion which typically occurs within 1 to about 6 hours. Upon reaction completion, the product can be isolated and purified by techniques well known in the art, such as filtration, extraction, evaporation, trituration, chromatography, and recrystallization.
Alternatively, for example, an anhydride (either symmetrical or mixed) can be employed in the reaction. Such anhydrides are formed by numerous methods known in art. Typically, about 1 to 1.5 molar equivalents of the anhydride and amine are used. It may be advantageous to use a suitable base to scavenge the acid generated during the reaction. Suitable bases include, by way of example, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, pyridine, sodium carbonate, potassium carbonate, sodium bicarbonate, and the like. The reaction can be carried out in a variety of solvents. The reaction is preferably conducted at from about 0° C. to about 60° C. until reaction completion which typically occurs within 1 to about 12 hours. Upon completion, the product can be isolated and purified by techniques well known in the art, such as filtration, extraction, evaporation, trituration, chromatography, and recrystallization.
Scheme B, steps b, depicts reduction of a compound of formula (6) or (8) to give a compound of formula I.
For example, a compound of formula (6) or (8) is contacted with a suitable reducing agent to give a compound of formula I. Suitable reducing agents are those which are capable of reducing an amide to an amine and include, borane reagents, such as borane dimethyl sulfide complex, hydride transfer reagents, such as aluminum hydride and lithium aluminum hydride, and the like. The reaction is carried out in a solvent, such as tetrahydrofuran or diethyl ether, typically using 1 to 10 equivalents of reducing agent. The reaction is generally conducted at from about 0° C. the refluxing temperature of the selected solvent and typically occurs within 1 to about 48 hours. The product can be isolated and purified by techniques well known in the art, such as quenching, filtration, extraction, evaporation, trituration, chromatography, and recrystallization.
Scheme B, as an optional step, not shown, an acid addition salt of a compound of formula I is formed using a pharmaceutically-acceptable acid. The formation of acid addition salts is well known and appreciated in the art.
In Schemes A and B, as an optional step, not shown, as will be appreciated by the skilled person, a compound of formula I in which R2 is hydrogen can be alkylated to give a compound in which R2 is not hydrogen. Methods for alkylating such secondary amines are will known in the art and discussed in Scheme C, step c, below.
In Schemes A and B, as will be appreciated by the skilled person, compounds of formula II are also prepared by the methods described in Schemes A and B using compounds of the formula (9) and (10), below:

An appropriate compound of formula (9) is one in which Y, R5 and R6 are as desired in the final product of formula II and an appropriate compound of formula (10) is one in which A is an activating group, as described above, and Y, R5 and R6 are as desired in the final product of formula II.
Starting material for Schemes A and B are prepared in the Schemes below. In the Schemes below all substituents, unless otherwise indicated, are as previously defined, and all starting material and reagents are well known and appreciated in the art.
Scheme C describes methods for preparing compounds of formula (1).

Scheme C, step a, depicts the reaction of an appropriate aldehyde of formula (24) and nitromethane to give the compound of formula (25). An appropriate aldehyde of formula (24) is one in which R1 is as desired in the final product of formula I. The reaction of the anion of nitromethane with aldehydes to give nitro olefins is well known and appreciated in the art. Modern Synthetic Reactions, H. O. House (2nd ed. The Benjamin/Cummings Publishing Company 1972).
For example, an appropriate aldehyde of formula (24) is condensed with nitromethane to give the compound of formula (25). Typically the reaction is carried out in the presence of an excess of nitromethane. The reaction is performed in a suitable solvent, such as tetrahydrofuran, nitromethane, and dimethyl sulfoxide. The reaction is performed using from about 1.1 to about 3 molar equivalents of a suitable base, such as sodium bis(trimethylsilyl)amide, potassium t-butoxide, sodium hydride, sodium acetate, triethylamine, N,N-diisopropylethylamine, ammonium salts, such as ammonium acetate. The reaction is carried out at temperatures of from about −20° C. to the reflux temperature of the selected solvent and generally require from 6 hours to 48 hours. The product of the coupling reaction can be isolated and purified using techniques well known in the art, including extraction, evaporation, chromatography and recrystallization.
Scheme C, step b, depicts the reduction of a compound of formula (25) to give a compound of formula (1) in which R2 is hydrogen.
For example, an appropriate compound of formula (25) is hydrogenated over a suitable catalyst, such as Raney® nickel or a palladium catalyst. When Raney nickel is used, the reaction is carried out in a suitable solvent, such as ethanol, methanol, water, and mixtures thereof. It may be advantageous to carry out the hydrogenation under acidic conditions, for example, using hydrochloric or sulfuric acid. When a palladium catalyst is used palladium-on-carbon is preferred and the reaction is carried out in a suitable solvent, such as ethanol, methanol, tetrahydrofuran, water, and mixtures thereof. It may be advantageous to carry out the hydrogenation under acidic conditions, for example, using hydrochloric, trifluoroacetic acid, or sulfuric acid. The reaction is generally carried out at temperatures of from ambient temperature to 70° C. The reaction is carried out with hydrogen at pressures of from 15 psi to 120 psi in an apparatus designed for carrying out reactions under pressure, such as a Parr® hydrogenation apparatus. The product can be isolated by carefully removing the catalyst by filtration and evaporation. The product can be purified by extraction, evaporation, trituration, chromatography, and recrystallization.
Alternately, for example, an appropriate compound of formula (25) is contacted with a suitable reducing agent. Suitable reducing agents include hydride transfer reagents, such as aluminum hydride and lithium aluminum hydride, and the like. The reaction is carried out in a solvent, such as tetrahydrofuran or diethyl ether, typically using 1 to 10 equivalents of reducing agent. The reaction is generally conducted at from about 0° C. the refluxing temperature of the selected solvent and typically occurs within 1 to about 48 hours. The product can be isolated and purified by techniques well known in the art, such as quenching, filtration, extraction, evaporation, trituration, chromatography, and recrystallization.
Additionally, an appropriate compound of formula (25) can be reduced in two steps to a compound of formula (1). For example, the vinyl group of a compound of formula (25) can be reduced using reagents such as sodium borohydride. The reaction is typically carried out using an excess of borohydride in a solvent, such as methanol, ethanol, isopropanol, water, and the like. The intermediate 2-nitroethyl compound can be isolated and purified by techniques well known in the art, such as quenching, filtration, extraction, evaporation, trituration, chromatography, and recrystallization. The intermediate 2-nitroethyl compound can then be reduced using a variety of methods, such as the hydrogenation and hydride transfer reagents as discussed above. Also, the intermediate 2-nitroethyl compound can be reduced using metals such as zinc to give the desired amine of formula (1) in which R2 is hydrogen.
Scheme C, step c, depicts the optional alkylation of a compound of formula (1) in which R2 is hydrogen to give a compound of formula (1) in which R2 is not hydrogen.
For example, a compound of formula (1) in which R2 is hydrogen is contacted with a suitable alkylating agent. A suitable alkylating agent is one which transfers a group R2 as is desired in the final product of formula I. Suitable alkylating agents include C1-C3 alkyl halides. The reaction is carried out in a suitable solvent, such as dioxane, tetrahydrofuran, tetrahydrofuran/water mixtures, or acetonitrile. The reaction is carried out in the presence of from 1.0 to 6.0 molar equivalents of a suitable base, such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, triethylamine, or N,N-diisopropylethylamine. The reaction is generally carried out at temperatures of from −78° C. to the refluxing temperature of the solvent. Generally, the reactions require 1 to 72 hours. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography, and recrystallization.
Alternately, for example, a compound of formula (1) in which R2 is hydrogen undergoes a reductive amination with an aldehyde or ketone which gives a compound of formula (1) in which R2 is not hydrogen. Suitable aldehydes include formaldehyde, acetaldehyde, propionaldehyde, and acetone. The reaction is carried out as described in Scheme A, step a.
In another alternate, for example, a compound of formula (1) in which R2 is hydrogen undergoes amide or carbamate formation followed by reduction to give a compound of formula (1) in which R2 is not hydrogen. Suitable aldehydes include formaldehyde, acetaldehyde, propionaldehyde, and acetone. The reaction is carried out as described in Scheme A, step a.
Scheme C, steps d and e, depict an alternative approach to preparing the compounds of formula (1) via formation of an amide using an appropriate compound of formula (7) and an appropriate amine of formula (26) to give an amide of formula (27), followed by reduction to give a compound of formula (1). An appropriate compound of formula (7) is as described in Scheme B. An appropriate amine of formula (26) is one which gives R2 as desired in final compound of formula I. The skilled person will recognize that many of the amides of formula (27) are commercially available and available in the art.
The amide formation and reduction in Scheme C are carried out as described in the Scheme B.
Scheme D describes methods for preparing compounds of formula (1) in which R1 is optionally substituted indol-3-yl.

Scheme D, step a, depicts the two-step reaction of an appropriate indole of formula (28) with oxalyl chloride followed by an appropriate amine of formula (26), R2NH2 to give a compound of formula (29). An appropriate indole of formula (28) is one in which Z′ represents optional substituents on the indole 2- and 4- to 7-positions as desired in the final product of formula I. An appropriate amine of formula (26) is as described in Scheme C, above.
For example, an appropriate indole of formula (28) is contacted with about 1 to 2 molar equivalents of oxalyl chloride to give an intermediate keto-acid chloride. The reaction is carried out in a suitable solvent, such a diethyl ether or tetrahydrofuran. The reaction is generally carried out at temperatures of from 0° C. to 40° C. and generally require from 6 hours to 48 hours. The intermediate keto-acid chloride product can be isolated and purified using techniques well known in the art, including extraction, evaporation, chromatography and recrystallization. Generally, the intermediate keto-acid chloride product is used directly after isolation. The intermediate keto-acid chloride product is contacted with an appropriate amine, R2NH2, as defined above and using the procedures described above.
Scheme D, step b, depicts the reduction of a compound of formula (29) to give a compound of formula (1) in which R1 is optionally substituted indol-3-yl.
For example, a compound of formula (29) is reduced using a suitable reducing reagent such as, lithium aluminum hydride to give a compound of formula (1) which R1 is optionally substituted indol-3-yl. The reaction is carried out in a solvent, such as tetrahydrofuran or diethyl ether, typically using 1 to 12 molar equivalents of reducing agent. The reaction is generally conducted at from about 0° C. the refluxing temperature of the selected solvent and typically occurs within 12 to about 48 hours. The product can be isolated and purified by techniques well known in the art, such as quenching, filtration, extraction, evaporation, trituration, chromatography, and recrystallization.
In Scheme D, step c, an appropriate indole of formula (28) is formylated to give a compound of formula (30). An appropriate indole of formula (28) is as described in step a, above.
For example, an appropriate indole of formula (28) is reacted with a suitable formyl transfer reagent, such as the Vilsmeier reagent formed from dimethylformamide. Generally, about 1 molar equivalent of formyl transfer reagent is used. The reaction is performed in a suitable solvent, such as benzene, dimethylformamide, tetrahydrofuran, or diethyl ether. The reaction is carried out at temperature of from about −70° C. to about 20° C. and generally require from 1 hours to 6 hours. The product of the reaction can be isolated and purified using techniques well known in the art. These techniques include extraction, evaporation, chromatography and recrystallization.
In Scheme D, step d, an appropriate indole of formula (28) is contacted with (CH3)2N—CH═CH—NO2 to give a compound of formula (30). An appropriate indole of formula (28) is as described in step a, above.
For example, an appropriate indole of formula (28) is reacted with 1-dimethylamino-2-nitroethylene. Generally, about 1 equimolar amounts of reagents. The reaction is performed in a suitable solvent, such as trifluoroacetic acid or dichloromethane containing about 2 to 15 equivalents of trifluoroacetic acid. The reaction is carried out at temperature of from about −70° C. to about 20° C. and generally require from 1 hours to 24 hours. The product of the reaction can be isolated and purified using techniques well known in the art. These techniques include extraction, evaporation, chromatography and recrystallization.
Scheme D, steps e and f, depict an the reaction of an aldehyde of formula (30) to give a nitro olefin of formula (31) and the reduction of the nitro olefin to give a compound of formula (1) in which R1 is optionally substituted indol-3-yl. These steps can be carried out using the methods described in Scheme C.
As will be appreciated by the skilled person, in steps not shown, the indole nitrogen of a compound of formula (1) can be substituted, as desired, using suitable amine protecting groups to give compounds in which R1 is 1-substituted indol-3-yl. Also as will be appreciated by the skilled person, in steps described in Scheme C, R2 groups which are not hydrogen can be introduced by various methods.
Scheme E describes methods for preparing compounds of formula (2) in which X is —O— or —S—.

Scheme E, step a, depicts the formation of an acetal of an appropriate compound of formula (11) to give a compound of formula (12). An appropriate compound of formula (11) is one in which X and R3 are as desired in the final compound of formula I. Such acetal formation reactions are readily accomplished by methods well known in the art. (Protecting Groups in Organic Synthesis, Theodora Greene (Wiley-Interscience)).
For example, a compound formula (11) is contacted under acid catalysis with an appropriate alcohol, HOR. An appropriate alcohol is one which gives an acetal with is stable to the reaction in step b and can be removed in step c to give a compound of formula (2). Appropriate alcohols include methanol, ethanol, propanol, 1,3-propane diol, ethylene glycol, and the like.
In Scheme E, step b, an appropriate compound of formula (11), (12), or (14) is reacted with an R4 group transfer reagent, as desired, to give a compound of formula (2), (13), or (15); respectively. Appropriate compounds of formula (11), (12), and (14) are ones in which X and R3 are as desired in the final product of formula I. A variety of reagents that transfers an R4 as desired in the final product are available and suitable for the reaction depicted in Scheme E. Such reagents include halopyridines, halopryidine N-oxides, allyl halides, C2-C4 alkanols, C2-C4 alkyl halides and sulfonates, fluorinated C2-C4 alkanols, fluorinated C2-C4 alkyl halides and sulfonates, optionally substituted phenyl having at least one fluoro or chloro atom, optionally substituted phenylsulfonyl halides or anhydrides, and optionally substituted benzyl halides.
For example, where the appropriate R4 group transfer reagent is a halide, sulfonate, or anhydride, an appropriate compound of formula (11), (12), or (14) is coupled under basic conditions to give a compound of formula (2), (13), or (15); respectively. The reaction is performed in a suitable solvent, such as acetonitrile, dimethylformamide, dimethylacetamide, tetrahydrofuran, pyridine, and dimethyl sulfoxide. The reaction is carried out in the presence of from about 1 to about 3 molar equivalents of a suitable base, such as potassium hydride, sodium hydroxide, sodium hydride, sodium carbonate, potassium carbonate, cesium carbonate, N,N-diisopropylethylamine, triethylamine, and the like. The reaction is carried out at temperature of from about −30° C. to about 100° C. and generally require from 6 hours to 48 hours. The product of the reaction can be isolated and purified using techniques well known in the art. These techniques include extraction, evaporation, chromatography and recrystallization.
Of course, when a halopyridine N-oxide is used the N-oxide is remove by reduction to give the R4 as desired in the final product of formula I. Such reductions are readily accomplished by the skilled person, and include catalytic reduction over palladium catalysts using hydrogen or ammonium formate in a suitable solvent such as methanol, ethanol, water, and mixtures thereof.
Alternately, for example, where the appropriate R4 group transfer reagent is an alkanol, the coupling can be carried out under Mitsunobu conditions which are well known in the art. The reaction is carried out in a suitable solvent, such as tetrahydrofuran and diethyl ether using a phosphine, such as triphenylphosphine or a resin bound phosphine and a dialkyl azodicarboxylate, such as diethyl azodicarboxylate, diisopropyl azodicarboxylate or di-t-butyl azodicarboxylate. The reaction is generally carried out at temperatures of from ambient temperatures to 60° C. The reaction generally requires from 1 hour to 12 hours. The product can be isolated by techniques well known in the art, such as extraction and evaporation. The product can then be purified by techniques well known in the art, such as distillation, chromatography, or recrystallization.
Scheme E, step c, depicts the deprotection of an acetal of formula (13) to give a compound of formula (2). Such deprotections are readily accomplished by methods well known in the art. (Protecting Groups in Organic Synthesis, Theodora Greene (Wiley-Interscience)).
For example, a compound formula (13) is contacted under acid under aqueous conditions to give a compound of formula (2).
In Scheme E, step d, a bromo compound of formula (15) is formylated to give a compound of formula (2).
For example, a compound of formula (15) is metalated by treatment with a metalation reagent such as butyl lithium. The reaction is performed in a suitable solvent, such as hexane, benzene, toluene, tetrahydrofuran or diethyl ether. The reaction is typically carried out in the presence of from about 1 to about 1.5 molar equivalents of a metalating reagent. The metalation reaction is carried out at temperature of from about −70° C. to about 20° C. and generally require from 1 hours to 6 hours. The metalated species is then treated with a formyl transfer reagent such as dimethylformamide or an alkyl chloroformate to give a compound of formula (2) or a alkoxycarbonyl compound which can be elaborated to an aldehyde as described herein. The product of the reaction can be isolated and purified using techniques well known in the art. These techniques include extraction, evaporation, chromatography and recrystallization.
Scheme F describes methods for preparing compounds of formula (2) from the versatile intermediate, compound (17), which readily prepared by acetal formation as described above.

Scheme F, step a, depicts an aromatic displacement reaction of an appropriate compound of formula (17) and an appropriate alcohol (R4OH) or an appropriate thiol (R4SH) to give a compound of formula (13) in which X is —O— or —S— are defined above in Scheme E. An appropriate compound of formula (17) is one in which R3 is as desired in the final product of formula I. In an appropriate alcohol (R4OH) or an appropriate thiol (R4SH), R4 is as desired in the final product of formula I, and includes C2-C4 alkyl alcohols and thiols, fluorinated C2C4 alkyl alcohols and thiols, optionally substituted phenols and thiophenols, optionally substituted benzyl alcohols and thiols.
For example, an appropriate compound of formula (17) and an appropriate alcohol (R4OH) or an appropriate thiol (R4SH) are coupled give a compound of formula (13). The reaction is performed in a suitable solvent, such as dimethylformamide, dimethylacetamide, and dimethyl sulfoxide. The reaction is performed using from about 1.1 to about 3 molar equivalents of an appropriate alcohol or thiol. The reaction is carried out in the presence of from about 1 to about 6 molar equivalents of a suitable base, such as potassium hydride, sodium hydroxide, potassium carbonate, sodium carbonate, or sodium hydride. The coupling is performed using a suitable catalyst, such as copper salts. The reaction generally requires from 6 hours to 48 hours. The product of the coupling reaction can be isolated and purified using techniques well known in the art. These techniques include extraction, evaporation, chromatography and recrystallization.
Scheme F, steps b-e, depict a number of reactions of an appropriate compound of formula (17), after metalation as described in Scheme E, step d, to give compounds of formula (18)-(21), respectively. In these steps an appropriate compound of formula (17) is one in which R3 is as desired in the final product of formula I and is not adversely affected by the metalation conditions of the reaction. Generally, these reactions are performed in the solvent used and at the temperature used to form the metalated species. The products of these reactions can be isolated and purified using techniques well known in the art, include quenching, extraction, evaporation, trituration, chromatography, and recrystallization.
For example, in Scheme F, step b, a metalated compound of formula (17) is contacted with an appropriate disulfide (R4S—)2, to give a compound of formula (18). An appropriate disulfide is one that gives R4 as desired in the final product of formula I and gives rise to compounds in which X is —S—. Appropriate disulfides include C1-C4 alkyl disulfides, optionally substituted phenyl disulfides, and optionally substituted benzyl disulfides. The reaction is performed using from about 1 to about 2 molar equivalents of an appropriate disulfide. The reaction is typically carried out in the same solvent used for the metallation and at temperatures of about −78° C. to about 50° C. The reaction generally require from 12 hours to 48 hours.
For example, in Scheme F, step c, a metalated compound of formula (17) is contacted with an appropriate sulfonyl fluoride (R4SO2F) to give a compound of formula (19). An appropriate sulfonyl fluoride is one that transfers R4 as desired in the final product of formula I and gives rise to compounds in which X is —SO2—. Appropriate sulfonyl fluorides include an optionally substituted phenyl sulfonyl fluoride. The reaction is performed using from about 1 to about 3 molar equivalents of an appropriate sulfonyl fluoride. The reaction is typically carried out in the same solvent used for the metallation and at temperatures of about −78° C. to about 0° C. The reaction generally require from 2 hours to 12 hours.
For example, in Scheme F, step d, a metalated compound of formula (17) is contacted with an appropriate acid chloride (R4C(O)Cl) to give a compound of formula (20). An appropriate acid chloride is one that transfers R4 as desired in the final product of formula I and gives rise to compounds in which X is —C(O)—. Appropriate acid chlorides include C2-C4 alkyl acid chlorides, fluorinated C2-C4 alkyl acid chlorides, optionally substituted phenyl acid chlorides, optionally substituted benzyl acid chlorides, and optionally substituted 5 to 6 membered monocyclic aromatic heterocycle acid chlorides. The reaction is performed using from about 0.8 to about 1.2 molar equivalents of an appropriate acid chloride. The reaction is typically carried out in the same solvent used for the metallation and at temperatures of about −78° C. to about 50° C. The reaction generally require from 1 hours to 12 hours.
For example, in Scheme F, step e, a metalated compound of formula (17) is contacted with an appropriate aldehyde (R4C(O)H) to give a compound of formula (21). An appropriate aldehyde is one that transfers R4 as desired in the final product of formula I and gives rise to compounds in which X is —CH(OH)—. Appropriate aldehydes include C2-C4 alkyl aldehyde, fluorinated C2-C4 alkyl aldehyde, optionally substituted phenyl aldehyde, optionally substituted benzyl aldehyde, and optionally substituted 5 to 6 membered monocyclic aromatic heterocycle aldehyde. The reaction is performed using from about 1 to about 3 molar equivalents of an appropriate aldehyde. The reaction is typically carried out in the same solvent used for the metallation and at temperatures of about −50° C. to about 50° C. The reaction generally requires from 4 hours to 24 hours.
As will be appreciate by the skilled person, compounds of formula (18)-(21) can undergo a number of other transformations which are depicted in Scheme F, steps f-i, to give, ultimately, compounds of formula I having various groups at X. These transformations are trivial and well within the ability of the skilled person. These transformations include oxidation of sulfides (step f) which can be accomplished by peroxide, peracids, and other reagents known in the art; reduction of a benzyl alcohol (step g) which can be accomplished by a variety of reagents, such as triethylsilane/trifluoroacetic acid; halogenation of a benzyl alcohol to give fluoro (step h) using reagents such as DAST and fluorinating reagents; reduction of a ketone (step i) using various hydride transfer reagents or oxidation of a benzylic alcohol (step i) which can be accomplished by manganese dioxide or Swern conditions.
In Scheme F, step j, compounds of the formula (13) and (18)-(23) are deprotected to give an aldehyde of formula (2) as described in Scheme E, step c.
Scheme G describes methods for preparing compounds of formula (5).

Scheme G, step a, a bromo compound of formula (15) is carboxylated to give a compound of formula (5) in which A is —OH.
For example, a compound of formula (15) is metalated as described in Scheme E, step d, and the metalated species is then treated with carbon dioxide to give a compound of formula (5) in which A is —OH. The product of the reaction can be isolated and purified using techniques well known in the art. These techniques include extraction, evaporation, chromatography and recrystallization.
Scheme G, step b, a bromo compound of formula (15) is alkoxyformylated using an appropriate chloroformate or carbonate to give a compound of formula (32). An appropriate chloroformate or carbonate is one that transfers an RO(O)C— group in which R is methyl, ethyl, or benzyl.
For example, a compound of formula (15) is metalated as described in Scheme E, step d, and the metalated species is then treated with about 1 to 3 molar equivalents of an appropriate chloroformate or carbonate. The reaction is typically carried out in the same solvent used for the metallation and at temperatures of about −78° C. to about 50° C. The reaction typically requires from 1 to 24 hours. The product of the reaction can be isolated and purified using techniques well known in the art. These techniques include extraction, evaporation, chromatography and recrystallization.
In Scheme G, step c, an appropriate compound of formula (33) is reacted with an R4 group transfer reagent, as desired, to give a compound of formula (32). An appropriate compound of formula (33) is one in which X and R3 are as desired in the final product of formula I. Reagents that transfers an R4 are as described in Scheme E.
For example, where the appropriate R4 group transfer reagent is a halide or anhydride, an appropriate compound of formula (34) is coupled under basic conditions with to give a compound of formula (33). The reaction is performed in a suitable solvent, such as dimethylformamide, tetrahydrofuran, or pyridine. The reaction is typically carried out in the presence of from about 1 to about 3 molar equivalents of a suitable base, such as sodium carbonate, potassium carbonate, cesium carbonate, N,N-diisopropylethylamine, triethylamine, and the like. The reaction is carried out at temperature of from about −30° C. to about 100° C. and generally require from 6 hours to 48 hours. The product of the reaction can be isolated and purified using techniques well known in the art. These techniques include extraction, evaporation, chromatography and recrystallization.
Alternately, for example, where the appropriate R4 group transfer reagent is an alkanol, the coupling can be carried out under Mitsunobu conditions which are well known in the art and described in Scheme E.
Scheme G, step d, an ester of formula (32) is deprotected to give a compound of formula (5) in which A is —OH. Such deprotections are readily accomplished by methods well known in the art. (Protecting Groups in Organic Synthesis, Theodora Greene (Wiley-Interscience)).
Scheme G, step e, a compound of formula (5) in which A is —OH is converted to a compound of formula (5) in which A is an activating group, such as acid halide, activated ester, activated amide, or anhydride. The formation of such activated intermediates is well known and appreciated in the art.
For example, an acid halide can be prepared by a variety of reagent such as oxalyl chloride, oxalyl bromide, thionyl chloride, thionyl bromide, phosphorous oxychloride, phosphorous trichloride, and phosphorous pentachloride; a mixed anhydride of substituted phosphoric acid, such as dialkylphosphoric acid, diphenylphosphoric acid, halophosphoric acid; of aliphatic carboxylic acid, such as formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, 2-ethylbutyric acid; an activated ester, such as phenol ester, p-nitrophenol ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester, 1-hydroxybenzotriazole ester; or activated amide, such as imidazole, dimethylpyrazole, triazole; are prepared by method which are well known and appreciated in the art. Such activated intermediates may be prepared and used directly or are prepared and isolated before use in the schemes above.
Scheme H describes methods for preparing compounds of formula (4).

Scheme H, step a, a bromo compound of formula (15) is converted to a nitrile of formula (35).
For example, a compound of formula (15) is treated with copper (I) cyanide to give a compound of formula (35). The reaction is performed in a suitable solvent, such as dimethylformamide. The reaction is typically carried out in the presence of from about 1 to about 3 molar equivalents of copper (1) cyanide. The reaction is carried out at temperature of from about ambient temperature to about 100° C. and generally require from 6 hours to 48 hours. The product of the reaction can be isolated and purified using techniques well known in the art. These techniques include extraction, evaporation, chromatography and recrystallization.
Scheme H, step b, a nitrile compound of formula (35) reduced to give a compound formula (4) in which R2 is hydrogen.
For example, a nitrile compound of formula (35) is contacted with sodium borohydride in the presence of cobalt chloride. The reaction is carried out in a suitable solvent, such as methanol, or ethanol. The reaction is generally carried out at temperatures of from 0° C. to 50° C. Generally, the reactions require 1 to 72 hours. The product can be isolated and purified by techniques well known in the art, such as extraction with aqueous acid, evaporation, trituration, chromatography, and recrystallization.
Alternately, for example, a nitrile compound of formula (35) is hydrogenated over a suitable catalyst, such as Raney® nickel. The reaction is carried out in a suitable solvent, when Raney® nickel is used as the catalyst, suitable solvents will generally contain ammonia, such as ethanol/ammonium hydroxide. The reaction is generally carried out at temperatures of from ambient temperature to 50° C. The reaction is carried out at pressures of from 15 psi (103 kPa) to 120 psi (827 kPa) in an apparatus designed for carrying out reactions under pressure, such as a Parr hydrogenation apparatus. The product can be isolated by carefully removing the catalyst by filtration and evaporation. The product can be purified by extraction, evaporation, trituration, chromatography, and recrystallization.
Scheme H, step c, a nitrile compound of formula (35) is converted to a amide of formula (36).
For example, a compound of formula (35) is treated with acid or base under hydrolysis conditions to give a compound of formula (36). The reaction is performed in a suitable solvent, such as ethanol, isopropanol, dimethylsulfoxide, each containing water. The hydrolysis of an aromatic nitrile to an amide is well known and appreciated in the art. The product of the reaction can be isolated and purified using techniques well known in the art. These techniques include extraction, evaporation, chromatography and recrystallization.
Scheme H, step d, depicts formation of an amide of formula (37) by reacting a compound of formula (5) and an appropriate amine of formula H2NR2 in a amide forming reaction. An appropriate amine of formula H2NR2 is one which gives R2 as desired in the final product of formula I. Suitable methods of forming amides are well known in the art and are described in Scheme B, above.
Scheme H, step e, a amide compound of formula (36) or (37) is reduced to a compound of formula (4). Such reductions of amides are readily carried out as described in Scheme B, above, and as known in the art.
Scheme H, step f, a compound of formula (2) and an appropriate amine of formula H2NR2 undergo reductive amination to give a compound of formula (4). Such reductive aminations are readily carried out as described in Scheme B, above, and by other methods known in the art.
As will be appreciated by the skilled person, the compounds of formula II are readily prepared by methods analogous to those described above.
The present invention is further illustrated by the following examples and preparations. These examples and preparations are illustrative only and are not intended to limit the invention in any way.
The terms used in the examples and preparations have their normal meanings unless otherwise designated. For example, “° C.” refers to degrees Celsius; “N” refers to normal or normality; “M” refers to molar or molarity; “mmol” refers to millimole or millimoles; “g” refers to gram or grams; “mL” refers milliliter or milliliters; “mp” refers to melting point; “brine” refers to a saturated aqueous sodium chloride solution; etc. In the 1H NMR, all chemical shifts are given in δ, unless otherwise indicated.